Parkinson disease (PD) is a common neurodegenerative disorder affecting more than 1 million people in North America. The cause of PD is unknown in most cases but environmental metal exposure may be a risk factor. The primary goal of this grant is to compare brains of South African manganese (Mn) miners to the brains of South African gold (Au) miners to investigate the hypothesis that workers with chronic exposure to Mn will have neuropathologic findings typical of early PD, to further clarify the role of environmental metal exposure in the pathogenesis of PD. To accomplish this goal, we will perform neuropathologic examinations of brains obtained from South African Mn miners and reference brains from South African Au miners. Neurons, astrocytes and microglia will be counted with stereology, following immunohistochemical staining with antibodies against NeuN, GFAP and CD68, in the following fixed brain regions: globus pallidus interna, substantia nigra pars compacta, locus ceruleus, and olfactory bulb. We will also attempt to correlate sterologic cell count with tissue Mn deposition in each region of interest. Distribution of Lewy bodies, Lewy neurites and alpha-synuclein aggregates, if any, will also be evaluated after tissues are stained with an antibody against alpha-synuclein. In addition, the number of neurons and the extent of gliosis or other markers of injury in miners exposed to Mn will be correlated with the reconstructed occupational Mn exposure as well as with clinical signs of parkinsonism from past neurological exams available through employment health files. The amount of alpha-synuclein and its aggregates will be quantified with Western blot in these same brain regions. Additionally, residual tyrosine hydroxylase (TH) will be determined in the striatum of miners. We will attempt to correlate alpha-synuclein aggregation and residual striatal TH in Mn miners with reconstructed occupational Mn exposure as well as clinical signs of parkinsonism from available employment health files. This project involves a unique international collaboration of American PD and Mn researchers and the South African National Institute of Occupational Health in the world's leading Mn producing country. PUBLIC HEALTH RELEVANCE: The results of this study will provide a better understanding of the relationship between metal exposure, specifically, manganese and Parkinson disease. Findings from this study may be translated into preventative measures to reduce the frequency of Parkinson disease.